TBX2

protein-coding

T-box transcription factor 2, the group of T-box transcription factors

Gene summary

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene product is the human homolog of mouse Tbx2, and shares strong sequence similarity with Drosophila omb protein. Expression studies indicate that this gene may have a potential role in tumorigenesis as an immortalizing agent. Transcript heterogeneity due to alternative polyadenylation has been noted for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_005994.4

Inheritance

ClinVar variants

P:6U:124B:36

Top phenotype

Vertebral anomalies and variable endocrine and T-cell dysfunction

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr17:61,399,843-61,409,466

External References & Databases

Ensembl (ENSG00000121068)

Transcript & Mutation Effects

hg38 • Region Span ~9.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

vertebral anomalies and variable endocrine and T-cell dysfunctionLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0032607

Submitter: Illumina

vertebral anomalies and variable endocrine and T-cell dysfunctionLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0032607

Submitter: ClinGen

The *TBX2* gene is located on chromosome 17 at 17q23.2 and encodes the T-Box transcription factor 2 protein, which acts as a transcriptional repressor. *TBX2* was first reported in relation to autosomal dominant vertebral anomalies and variable endocrine and T-cell dysfunction (VETD) in 2018 (Liu et al., PMID: 29726930). VETD is characterized by cardiac anomalies, skeletal malformations, immune deficiency, endocrine abnormalities, developmental delay, behavioral problems, and facial dysmorphism. Evidence supporting this gene-disease relationship includes case-level data and experimental evidence. Three missense variants and 1 nonsense variant that have been reported in six patients in three publications are included in this curation (PMIDs: 29726930, 35311234, 36733940). An additional case was published in PMID: 39843441 (2025) but insufficient phenotypic details were available to include the case in this curation. This gene-disease relationship is supported by experimental data including biochemical function, protein interaction, expression, and model organism data. For biochemical function, *Tbx2* and *Tbx3* share 90% amino acid similarity within the T-box domain and function predominantly as transcriptional repressors (PMID: 29726930). TBX3 is definitively associated with ulna-mammary syndrome. An electromobility shift assay (EMSA) conducted by Habets et al. (2002) demonstrated that Nkx2.5 and *Tbx2* form a large ternary complex (protein interaction), which represses ANF promoter activity (PMID: 12023302). Chromatin immunoprecipitation experiments (ChIP) demonstrated that *Tbx2* binds to Grem1 limb regulatory element (PMID: 23633963):; however, this finding was not scored, as GREM1 is not listed as disease-associated in OMIM. Immunofluorescence staining using a mouse monoclonal antibody against *TBX2*, as performed by Sizarov et al. (2011) demonstrated *TBX2* expression in the human heart (PMID: 21403123). Harrelson et al. (2004) reported that homozygous mouse embryos are embryonically lethal due to cardiovascular insufficiency; however the score was downgraded as heterozygous mice appear normal and fertile (PMID: 15459098). In summary, there is limited evidence to support the relationship between *TBX2* and autosomal dominant VETD. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification is approved by the ClinGen Syndromic Disorders GCEP on the meeting date April 22, 2025 (SOP Version 11).

vertebral anomalies and variable endocrine and T-cell dysfunctionMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032607

Submitter: PanelApp Australia

vertebral anomalies and variable endocrine and T-cell dysfunctionSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032607

Submitter: Labcorp Genetics (formerly Invitae)

vertebral anomalies and variable endocrine and T-cell dysfunctionLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0032607

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Vertebral anomalies and variable endocrine and T-cell dysfunctionAD

Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Craniofacial; Endocrine; Musculoskeletal; Neurologic

Intervention: Allergy/Immunology/Infectious; Endocrine

Rationale: The condition can include endocrine dysfunction, and awareness may allow prompt diagnosis and management; Immune deficiency has been described, and awareness may allow preventative measures and prompt treatment of infections

Refs: 29726930

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TBX2 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 100

not providedTotal: 36

TBX2-related disorderTotal: 26

Vertebral anomalies and variable endocrine and T-cell dysfunctionTotal: 22

Inborn genetic diseasesTotal: 1

MicrocephalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005994.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	25 clinvar	2 clinvar	30
missense		4 clinvar	120 clinvar	5 clinvar	4 clinvar	133
nonsense			1 clinvar			1
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)		1 clinvar				1
Total	0	6	124	30	6	166

Highest pathogenic variant AF is 0.000050998584

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005994.4	RefSeq	NP_005985.3	7	MANE Select
ENST00000240328.4	Ensembl	ENSP00000240328.3	7	MANE Select
ENST00000419047.5	Ensembl	ENSP00000404781.1	2	Standard
ENST00000964761.1	Ensembl	ENSP00000634820.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tbx2a	Danio rerio	Structure: pronephric distal late tubule Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

tbx2a

Danio rerio

Structure: pronephric distal late tubule

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Heart Development
Kit receptor signaling pathway
tumor suppressor arf inhibits ribosomal biogenesis

Biological Process

negative regulation of transcription by RNA polymerase II
heart looping
outflow tract septum morphogenesis
outflow tract morphogenesis
endocardial cushion morphogenesis

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
DNA binding
protein binding

Cellular Component

nucleus
transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000240328
Coding exons: 7
Length: 9571
Individuals with no LoFs: 119725
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 119726
p: 0.00000418

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.54	288	371	0.775	0.0000206	4454
Missense (PolyPhen)		130	177.36	0.73297		2021
Synonymous	1.11	151	169	0.892	0.0000103	1535
Loss of Function	3.86	1	19.3	0.0518	0.00000104	229

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000056	0.000056	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the transcriptional regulation of genes required for mesoderm differentiation. Probably plays a role in limb pattern formation. Acts as a negative regulator of PML function in cellular senescence. May be required for cardiac atrioventricular canal formation. {ECO:0000269|PubMed:22002537}.;

Recessive Scores

pRec: 0.228

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.994

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium